"Molecular Repair of the Brain":
A Scientific Critique

by Gregory M. Fahy, Ph.D.

The October, 1989 (vol. 10(10)) issue of Cryonics magazine carried an
impressive and seminal article by Dr. Ralph Merkle entitled "Molecular
Repair of the Brain" (pp. 21-44) [later revised and published in the January
and April 1994 issues of Cryonics]. One index of the influence of this
article is its citation by Arthur C. Clarke in his November, 1990 book, The
Ghost from the Grand Banks (Bantam; pp. 221-222, 259-260), which mentions
both Merkle and Alcor (complete with an address) by name. The importance of
this paper lies in its attempt to demonstrate the likely feasibility of cryonics
through a series of logical and mathematical arguments. Such an attempt, if
successful, should send doubting cryobiologists packing and make the world safe
for cryonics forever. Dr. Merkle's article, therefore, should be evaluated carefully
and honestly by cryobiologists. Since I am a cryobiologist, and one who likes
to consider new ideas, I have decided to undertake the task of providing such
an evaluation, and the present article contains the results of this evaluation.
Unfortunately for the readers of this periodical, I must report that the conclusion
of my critique will be that Dr. Merkle's attempt to provide persuasive arguments
for cryonics fails in a number of basic ways.

The Problem of Chemistry

Merkle notes, quite correctly, that "The thawing process. . . causes damage
and, once thawed, continued deterioration will proceed unchecked by the mechanisms
present in healthy tissue. This cannot be tolerated during a repair time of
several years" (p. 32). For this reason, he notes that "it seems likely that
repair will take place when the tissue is still frozen" (p. 30). Although he
says that temperature of repair is left open, he clearly favors repair at temperatures
below the glass transition temperature, e.g., at liquid nitrogen temperature.
For example, there are references to "an assembler operating at (perhaps) liquid
nitrogen temperatures" (p. 30), and "Fractures made at. . . temperatures below
the glass transition temperature" (pp. 33-34). He also makes the following general
statement: "it seems unlikely that reducing the temperature will create a barrier
that will inherently require longer synthesis times. Assemblers are basically
mechanical in nature, and so they can be designed to operate across a broad
range of temperatures. If anything, the reduction in thermal vibration as a
consequence of reduced temperature should allow more accurate positioning and
facilitate, rather than hinder, the assembler-based synthesis process." The
same basic idea has been restated also in two subsequent documents by the same
author (an as-yet unpublished update and revision of "Molecular Repair of the
Brain" renamed "The Technical Feasibility of Cryonics," and a short article
called "Cold Starting" in the November, 1990 issue of Cryonics (vol.
11(11), p. 11).

There is just one problem with sub-Tg repair: physical law! The fatal error
is that although assemblers may be "basically mechanical in nature," what they
do is not. What they are supposed to do is chemistry. At normal temperatures,
this is clearly reasonable: enzymes do chemistry all the time. But enzymes do
not work below Tg, and neither will assembler-induced chemical modifications.
Enzymes take advantage of thermal energy that is already available within the
reacting species to supply the activation energy required for chemistry (the
making or breaking of covalent bonds) to occur. Below Tg, this activation energy
is not present [1].

The breaking and making of chemical bonds under these circumstances can only
be achieved mechanically: by ripping atoms from other atoms and/or by slamming
or jamming atoms into other atoms with sufficient force as to provide the equivalent
of the ordinary thermal activation energy. (Conceivably, spectroscopic approaches
could also be used in some cases, but, most likely, not as a general rule.)
"Slamming" would involve accelerating the reacting species to velocities comparable
to (and perhaps greater than) their velocities at normal body temperature. "Jamming"
would involve a vice-like compression of molecule against molecule so as to
overcome intermolecular repulsions and thus catalyze the reaction. However,
the latter is the rough equivalent of increasing the local hydrostatic pressure,
and it appears that absolutely enormous pressures would generally be required
to drive chemical reactions at -196C. To give one indication: Whalley and colleagues
[2] have shown that pressures on the order of 15,000 atmospheres are required
to convert ice into amorphous solid water at liquid nitrogen temperature, and
this is a reaction that involves no chemistry! This reaction also involves a
decrease in volume. Driving reactions that result in a net increase in
volume in this way might not be possible. This seems to leave the "slamming"
approach as the main possibility.

But the "slamming" approach and the "jamming" approach are fundamentally similar,
the main difference being the time scale over which energy is applied. In any
case, how will the accelerations required for this approach be produced? At
a minimum, it seems to me, one must rip the desired molecule free from its embedding
medium (without hurting it), attach it to an assembler arm, orient it with extreme
precision on that arm in some fashion, and then slam it against the desire reactant,
also perfectly oriented on a second assembler arm. The basic problem that arises
from these requirements is: How can you attach each of the reacting molecules
to the assembler arms using only forces weaker than covalent bonds in such a
way that the force of the collision, which must be powerful enough to make or
break covalent bonds, does not dislodge them? (This will be an especially large
problem for smaller molecules.) Another important complication is waste heat
and the limitations it may put on assemblers: How much waste heat will be generated
during the acceleration of the assembler arms to sufficiently high velocities,
and what is the likelihood that this waste heat will accidentally lead to local
warming and diffusion or to the catalysis of some undesired reaction?

The opposite problem is: how does one grip a molecule on both ends in just
the right way as to be able to rend it asunder at exactly the correct bond in
every case? The answer is likely to be: one doesn't.

Possibly some technique in which harmonic oscillations of progressively greater
magnitude are mechanically induced between individual atoms could break selective
bonds and begin to approach these problems. But the problem is, nobody knows.
Merkle's paper simply fails to appreciate the fundamental problems of doing
chemistry on stable molecules below Tg, and one is left with only wild speculations
about how such a problem could even be approached in principle. It thus seems
to be something of an understatement to say that Merkle's approach of sub-Tg
repair (or even near-Tg repair) falls short of providing convincing evidence
for the technical feasibility of cryonics. Solving these problems seems to be
not just a matter of engineering, but also of creating an entirely new branch
of chemistry (or materials science), i.e., cryomechanical chemistry, to use
as a basis for the engineering that is needed. But it is by no means obvious
that it is possible, even in principle, to duplicate room temperature chemistry
using only mechanically-driven reactions at sub-Tg temperatures. At these temperatures,
we are not dealing with the kind of concept Feynman and Drexler have considered,
in which it is only necessary to position atoms appropriately and lean on them
just a little to get what you want. This is not chemistry as cells and as nature
know it. It is therefore quite obviously inappropriate to assume that normal
biological repair processes provide anything comparable to a "proof of principle"
that repair can be effected below Tg.

I believe Merkle's response to this problem may be to disassemble the frozen
brain into its individual molecules, warm them to room temperature individually
to permit them to react, and then to cool them back to liquid nitrogen temperature
and reassemble them at that temperature back into the intact, repaired brain.
But even this scenario is doubtful. It supposes that the brain is like a house
made of bricks, which only need to be stacked next to each other to complete
the edifice. The reality, however, is that there is a significant degree of
covalent bonding between many of the molecular components of the brain (e.g.,
membrane proteins are linked to the cytoskeleton, which in turn is linked to
organelles, and so forth). It seems unlikely that an entire brain can be disassembled
and reassembled at liquid nitrogen temperature without requiring the performance
of any chemistry at that temperature, even without considering the issue of
molecular repairs. Another suggestion Merkle has proposed informally is to use
free radical chemistry. Unfortunately, once again, it is far from clear that
free radical chemistry can entirely or even mostly duplicate ordinary, thermally-driven
chemistry.

Problems of Physics

On page 39, Merkle says "we must generate a plan for reassembly of the tissue
components (the molecules) back into the healthy state. . . that is, we must
determine how to actually rebuild the healthy tissue." The meaning of this is
explained on page 37 by, for example, the following: "If the initial data base
describes tissue with swollen or non-functional mitochondria, then the revised
data base should be altered so that it describes fully functional mitochondria."
(This idea is repeated also in "The Technical Feasibility of Cryonics.") Confirmation
that this is what Merkle actually proposes be done (i.e., restoration of a healthy
functional state at sub-Tg temperatures) is given by Merkle's "Cold Starting"
article.

Unfortunately, this approach is fundamentally nonsensical for a variety of
reasons. The simplest of these is simply that tissue cannot exist in a healthy,
functional state at -196C! For one thing, a functional mitochondrion contains
liquid water and no cryoprotectant. Even if such a state (in vitreous form)
could be created at very low temperatures, it would revert to a mitochondrion
containing massive amounts of internal ice within microseconds or less on warming
(hence Merkle's proposal in "Cold Starting" for a means of warming fast enough
to outrun this crystallization process!).

The more basic and general point is that some kinds of repair would be extraordinarily
difficult, futile, or even counterproductive to carry out at the lowest, most
protective temperatures for fundamental physical reasons. Consider the following
examples.

Osmotically-Induced Cellular Shrinkage. Slow freezing causes cell volume
reduction, which in turn may cause the reduction of cellular surface area and
a resulting extrusion of lipids and proteins from the membrane. Extruded lipids
and proteins cannot be reinserted into the membrane until the cell volume is
once again increased because there is no room for them. Restoring cell volume
while the cell is in the vitreous state would be a seemingly ridiculous and
superfluous task to attempt, and would again create a cell whose interior will
freeze within a fraction of a second during warming!

Phase Transitions. Low temperatures and membrane dehydration per se
cause membrane lipid species to crystallize or undergo HexII reorganizations.
This is therefore the natural state of these lipids at the prevailing temperatures.
Any attempt to reorder the membrane lipids into a lamellar phase will lead to
spontaneous re-separation of these phases either at the prevailing temperatures
or on warming. Thus, simply "repairing" this membrane defect at cryogenic temperatures
would be futile. Introduction of alien lipid species to prevent re-separation
would be problematic due to the absence of room in the membrane for such species
and the need to subtract native lipid to make room. These changes would all
have to be reversed later, and might create more problems than the original
phase separations.

Denaturation. Any denatured proteins will also prefer to be denatured
under the prevailing conditions. Renaturing them will tend to lead to re-denaturation
as temperatures inevitably rise later on.

Changes in Tissue Volume: Thermal Expansion vs. Brittleness & Elasticity.
A fracture represents anisotropic contraction of cerebral tissue due to temperature
reduction. Local rips in axons may arise for similar reasons. To fill in gaps
caused by the inherent thermal contraction of cerebral tissue may create a problem
when the temperature is raised and all of the existing structure, both the native
structure and the added structure, is inevitably forced to expand: expansion
lesions such as buckling and shearing of axons may replace the previous contraction
lesions. Likewise, many axons may be very stretched while frozen. Destretching
them by adding material to them could cause the same buckling problem when warming
occurs. Finally, tissue will be brittle below Tg and may be brittle even at
temperatures moderately above this. Physically moving structures around under
such conditions may damage them, and attempting to close a fracture by physically
forcing the two sides together is liable to rip structures on both sides of
the gap. Thus, some repairs made below Tg could induce the need for more repairs!

Incidentally, the thermal contraction-expansion cycle may also make Merkle's
"Cold Start" fail: even if the heating rates he wishes to achieve could be attained,
the result would quite possibly be a brain macerated or exploded from the stresses
of expanding its volume by several percent in a one microsecond interval. (Consider
the kinetic energy of brain tissue expanding outward at a speed of 0.5 cm/microsecond,
or, in other units, 18,000 km/hr!)

Problems of Power

How will nanomachines be powered? No comments from Merkle. At body temperature,
nanomachines could be powered by chemical energy the way metabolism is powered.
But at -135C? This is not just a detail to be left to future designers: it is
a point of principle. Is it feasible in principle to power complex molecular
manipulations (not even chemistry per se, but just physical manipulations)
at cryogenic temperatures? How can energy be translated from the macroscopic
to the molecular level? Without answers to these questions, the central idea
of Merkle's paper stands on a very flimsy foundation.

Presumably the power would have to be supplied via electrical cables or sliding
rods going in through the vascular system. How much power is needed? Can it
be supplied on wires small enough to thread through capillaries without warming
the tissue through resistive (or frictional) heating?

Problematic Time Estimates

On pages 29-31, Merkle tries to estimate the time required for the repair of
individual molecules. He does this by multiplying the in vivo synthesis
time by 10 to account for the fact that not only molecular synthesis but also
computations about such synthesis will be needed. He then notes, on page 30,
that "the times for the various biological synthesis steps give here must be
viewed as general 'proofs of principle' times rather than specific estimates
of the actual time that will be required by an assembler operating at (perhaps)
liquid nitrogen temperatures."

But in no way is the time for biological processes a "proof of principle" for
estimated cryogenic repair times: the biological processes depend on DIFFERENT
PRINCIPLES than the repair processes, both in terms of the mode of operation
(diffusion vs. conveyance) and in terms of the power supply. The biological
systems, at best, tell us how long molecular reactions take under one set of
conditions. However, without more detailed calculations (which, as indicated
above, may be impossible), the biological time scales and the nanotechnological
repair time scales (assuming that nanotechnological repair is possible at -196C
in the first place) cannot be related to one another. Assuming that the two
time scales are even in the same ballpark amounts to pure handwaving. This invalidates
the entire discussion of the time required for repair, which is a central point
of the paper.

Merkle does not really address the issue of determining WHERE molecules ought
to be and carrying out the actual procedure of repositioning them. It could,
for a variety of reasons, be time-consuming to figure out where to place a molecule
if it is misplaced, especially since placing one molecule influences the proper
placement of subsequent molecules. Consider that image analysis systems with
good resolution store individual images at 1-3 megabytes or more per 2-D frame,
exclusive of any analysis of the image. How many 2-D or 3-D images would be
necessary to carry out the needed repairs? Possibly a very very large number,
with correspondingly long times required for analysis.

The Problem of Vagueness

Merkle says, on page 40, "We will not examine the problem of generating a feasible
assembly sequence here. . . [but] it should be clear that it is indeed possible
to build living tissue. It is, after all, done by every living creature on the
planet. It also follows from the general thesis of nanotechnology: that the
construction of almost any chemically stable object that has been specified
to the atomic level is feasible. The revised structural data base clearly specifies
such an object (the brain) and specifies its structure in precise molecular
detail. Its construction should therefore be feasible, particularly when we
consider that existing biological systems already demonstrate 'proof of principle.'"

Thus, Merkle's paper does not seek to tell us how to repair a frozen brain.
It seeks only to describe peripheral issues of information content, computational
speed, etc. But it is hard to evaluate the possibility of repair if no actual
suggestions for repair are give. We have already exploded the analogies noted
in the preceding paragraphs: the workings of living systems have nothing to
do with the problem of constructing a brain at cryogenic temperatures, and the
tenet that specified structures can be built does not imply that specified structures
can be built under impermissive conditions such as in black holes, stars, or
vats of liquid nitrogen. Merkle says, on page 37, "if any cracks are present
in the initial data base (describing the frozen tissue) then the revised data
base (describing the healthy tissue) should be altered to remove these cracks."
But "removing these cracks" is a non-trivial exercise, and we are told nothing
about how this might be possible. In the end, we are left only with an apparently
unsupportable assertion that it should be possible. And this is the problem
that cryobiologists have had with cryonics all along.

Problems of Biology

On page 38, Merkle says "all current estimates of tissue 'viability' based
on functional criteria [are] irrelevant." However, functional damage is related
to structural damage. The greater the functional loss, the greater the structural
loss, and the less likely it is that the previous structure can be inferred.

Conclusions

Ralph Merkle has written an excellent paper which attempts to identify important
issues of the repair of frozen brains. He deserves praise for his great intellectual
effort and for many of his results. From the point of view of a cryobiologist,
however, Merkle's analysis falls far short of being convincing. It is based
on a number of assumptions that have dubious validity, and it fails to be specific.
While the present critique by no means rules out the possibility of developing
repair technology for frozen brains, it may help to clarify why the disagreements
between cryonicists and cryobiologists are not likely to be settled by Merkle's
paper.

References

1. Just below the glass transition temperature, available thermal energy is
insufficient to drive even diffusive processes, but ordinary biochemical reactions
require much more energy than does diffusion. Thus, the temperature below which
ordinary chemistry becomes almost impossible is likely to be considerably higher
than the glass transition temperature.

Dr. Merkle's Response

A Brief Summary

Greg Fahy recently (February, 1991) wrote a critique of "Molecular Repair of
the Brain" (originally published in the October, 1989 Cryonics, and under
continuous revision). To provide orientation for the reader who might not have
read that article, or whose memory of it might be hazy, a brief summary is in
order. It said that the frozen human brain could be repaired by the following
general approach: 1) Digitize the frozen structure. A sufficiently accurate
digitization for any purpose considered here would be provided by giving the
coordinates and orientation of every major molecule in the brain; 2) Once a
complete description of the frozen structure is available in digital format,
the description can be manipulated and revised to eliminate the damage; 3) Once
we have a digital description of a healthy human brain, we can then use that
description as a blueprint to rebuild the original.

The most obvious concern raised by this strategy is the rather massive amount
of raw information and the large amount of computer power being used. The fairly
long sections of the paper looking at projected future memory and computational
capacities were intended specifically to address that issue. Dr. Fahy's statement
that these issues are "peripheral" is wrong, for they are quite central. The
claim that computer power of the magnitude required will likely be available
in the future is not immediately obvious. If we expect people to believe this
claim, it must be supported by a careful analysis of the relevant facts.

The next problem is how to obtain the necessary information. A simple "divide
and conquer" strategy, in which the human brain is divided into pieces small
enough that they can be directly analyzed by the use of high resolution imaging
technology (e.g., nanotechnology) was proposed and should be quite adequate.

The paper did not discuss in any detail how "nanotechnology" works, but simply
provided some general reasons for believing it is plausible and references for
further reading. A detailed discussion of nanotechnology would require writing
a rather detailed technical book. Fortunately, Eric Drexler is currently writing
exactly such a book. The early drafts look very good. Many of Dr. Fahy's questions
really concern the nature and limitations of nanotechnology, so having a detailed
technical description of the subject will be very helpful in creating a common
framework within which to carry out further discussions.

The final concern is how to build a structure with atomic precision, given
the blueprint. Here, the paper concludes that there are strong arguments supporting
the general idea that this should be feasible and did not pursue the technical
issues further. The argument that it should be possible to build human brains
because they have in fact been built is very strong, and it would have required
significant additional work to provide a sufficiently detailed analysis of the
construction process to provide a better argument.

An issue which I view as completely irrelevant, but which causes some people
concern, is the retention of the "original" atoms. The claim that the original
electrons, protons, and neutrons are somehow vital to our continued existence
strikes me as absurd. Despite my opinions, some quite intelligent people take
the opposite view. As a consequence, the paper examined the technical feasibility
of retaining the original atoms, and concluded that this retention (while somewhat
increasing the technical difficulties that must be dealt with) would in fact
be feasible.

It is interesting that Dr. Fahy's criticisms are largely concerned with the
section of the paper that was not written, the section on synthesis. In several
instances, in the absence of a specific proposal in the paper, Dr. Fahy invented
a specific proposal and then criticized it. The whole section discussing "jamming"
and "slamming" is of this nature.

This form of criticism suffers because the critic's proposed solution to the
perceived problem is in fact a proposal of the critic. It is not surprising
that such proposals are often found wanting. . . . The underlying criticism
is that the original proposal has not provided sufficient detail to persuade
the critic, so the critic has felt obliged to invent something.

Dr. Fahy appears to agree that the synthesis of large structures (e.g., a human
brain) will be feasible. His criticisms have focused rather specifically on
the suggestion that such synthesis be done at low temperature (e.g., perhaps
130 to 140 Kelvins).

Some General Approaches to Repair

Before addressing the specific issues surrounding low temperature synthesis,
it would be advisable to discuss the general issues involved in synthesis at
any temperature, and the kinds of structures that might prove satisfactory.
The following taxonomy is not intended to be exhaustive, but is intended to
provide the reader with a feeling for the range of possibilities available.

1) The least demanding approach would be to build an "artificial brain" using
the digitized information provided by the analysis of the frozen brain. This
approach allows the selection of the simplest technology available which can
adequately support consciousness and human thought. While still controversial,
it is very likely that this approach will be technically feasible at some point
in the future.

The second class of methods seek to build an actual human brain, on the grounds
that we have a high degree of confidence that a human brain can support consciousness
and human thought. Rather than building a human brain directly, however, we
actually build a structure which closely resembles the desired structure but
which is, for some reason, stable. That is, the human brain is in a constant
state of dynamic change. Directly building a structure which is in a state of
constant dynamic change is difficult, so instead we build a static structure
which closely resembles the dynamic structure at some specific point in time.
The reason for building a static structure is the presumption that it will take
some time to build, and that a dynamically changing structure would deteriorate
during the synthesis time. The static structure won't move while it's being
built, so we can take as long as we wish to complete the construction. The obvious
methods of doing this are:

2) Synthesize the structure at low temperature.

3) Synthesize the structure in the dehydrated state.

4) Synthesize the structure in a normal "wet" state, but stabilize all major
macromolecules by chemical means (cross linkages, etc.). This might be called
"full stabilization."

5) Synthesize the structure in a normal "wet" state, but use minimal stabilization
aimed primarily at the membranes (by, e.g., simple mechanical supports), prevent
the entry of oxygen or other reactive compounds, and allow "harmless" diffusion
to take place. Note that with intact membranes, diffusion outside of well defined
compartments will not take place. Some additional stabilization might be required,
but the objective in this approach is to stabilize as little as possible. This
might be called "minimal stabilization."

Each of methods (2) through (5) has a "start-up" requirement. If synthesis
is done at low temperature, then the temperature must be somehow raised. If
synthesis is done in the dehydrated state, then water must be added in a controlled
way. If chemical stabilization is used, then the stabilizing agents must be
removed, presumably in some appropriate sequence. If minimal membrane stabilization
coupled with low oxygen content is used, then oxygen levels (and other reactive
compound levels) must be restored and the membrane supports removed.

Finally, we could adopt an approach that takes maximum advantage of the existing
technology base: guided growth. In this method, we build the dynamic final structure
through a series of dynamic intermediate states, much as an actual human brain
is synthesized today by natural methods.

6) Synthesize the structure using the same general intermediate states that
are used during normal growth. Achieve selectivity by placing key cellular activities
under the control of an on-board computer. Thus, the bulk of the cell's metabolic
machinery would be identical to that of a normal cell, but where a normal cell
would spontaneously initiate cell division, the "controlled" cell would be unable
to initiate cell division unless the trigger for division were produced by the
on-board computer. Changes in cellular shape and movement would likewise be
under on-board computer control, as well as the growth of synapses, etc.

Although superficially resembling the growth of a normal person, this process
would in fact be carefully controlled and planned. In simple organisms the growth
of every single cell and of every single synapse is determined genetically.
"All the cell divisions, deaths, and migrations that generate the embryonic,
then the larval, and finally the adult forms of the roundworm Caenorhabditis
Elegans have now been traced."[2]. "The embryonic lineage is highly invariant,
as are the fates of the cells to which it gives rise"[1]. The appendix to reference
[1] says: "Parts List: Caenorhabditis elegans (Bristol) Newly Hatched
Larva. This index was prepared by condensing a list of all cells in the adult
animal, then adding comments and references. A complete listing is available
on request. . ." The adult organism has 959 cells in its body, 302 of which
are nerve cells[3].

The same principles apply in many insects. Grasshoppers, for example, have
about 50,000 neurons whose development is invariant. Other insects have significantly
more neurons.

Building a specific biological structure using this approach would require
that we determine the total number and precise growth patterns of all the cells
involved. The human brain has roughly 10-12 nerve cells, plus perhaps ten
times as many glial cells and other support cells. While simply encoding this
complex a structure into the genome of a single cell and then expecting that
cell to grow into the final structure might prove to be overly complex, it would
certainly be feasible to control critical cellular activities by the use of
on-board nanocomputers. That is, each cell would be controlled by an on-board
computer, and that computer would in turn have been programmed with a detailed
description of the growth pattern and connections of that particular cell. While
the cell would function normally in most respects, critical cellular activities,
such as replication, motility, and synapse growth, would be under the direct
control of the on-board computer. Thus, as in C. Elegans but on a larger
scale, the growth of the entire system would be "highly invariant." Once the
correct final configuration had been achieved, the on-board nanocomputers would
terminate their activities and be flushed from the system as waste.

Tradeoffs

The six approaches mentioned here have different technical and philosophical
tradeoffs which will appeal to different people. Which approach is "best" is
a question which cannot be answered on purely rational bases. A process more
akin to an opinion poll is required. Those familiar with a specific technology
will naturally be more comfortable with methods in which that technology is
prominently used. Those with more conservative philosophical opinions will quite
naturally exclude some approaches, even at the cost of some increased technical
complexity.

Dr. Fahy, for example, would probably be most comfortable with "guided growth,"
for this makes maximal use of existing (proven) technology. On the other hand,
for someone worried that "guided growth" might produce a "mere copy," frozen
synthesis or fully stabilized chemical synthesis offers the most precise ability
to restore the structure with atomic precision.

Building an artificial brain is the simplest approach technically and would
therefore be attractive to those most concerned about technical feasibility.
This technical simplicity is gained by relaxing the philosophical criteria,
which is a tradeoff that some will not wish to make.

As can be readily seen, the debate about which of these general approaches
to use includes factors well beyond the technical issues. A desirable goal would
be to show that the most philosophically restrictive objectives are technically
feasible, for such a proposal could be used as a "least common denominator"
by everyone. This, presumably, would require a highly precise synthesis technique,
and would thus favor either frozen synthesis or fully stabilized chemical synthesis.
An interesting question is the degree of general acceptance of minimally stabilized
chemical synthesis. This approach provides a number of significant technical
simplifications and, if it were viewed as generally acceptable, might serve
as a reasonable "least common denominator."

In minimally stabilized chemical synthesis the original molecules would be
restored (thus satisfying the concerns of those who wish restoration of the
same atoms), but they would be allowed to move in accordance with diffusive
forces as they might normally move in a living person. Individual membranes
would be anchored (positionally stabilized) by a framework introduced for the
purpose. Thus, repair would restore the original person with the original cellular
structure and the original molecules, but the molecules would have been allowed
to diffuse within their cellular compartments (or diffuse two-dimensionally
within a membrane) much as they would normally do.

Computer Analysis is Fundamental

All these methods first use digitization of the human brain and revision of
the digitized information to "repair" damage. Changing bits in a data base is
a much more general and uniform method of "repair" than attempting to engage
in actual physical repair of a specific form of damage using a specific physical
repair technique. Given the severe level of damage that might occur when significant
pre-suspension injury has taken place, especially when this is compounded by
a suspension performed under adverse or sub-optimal conditions, it seems most
attractive to digitize the entire structure first rather than to attempt the
direct physical repair of specific forms of damage using specific techniques.
Such direct physical repair techniques could be overwhelmed by the many synergistically
interacting forms of injury that are likely to take place in many current suspensions.

Chemistry at Low Temperatures: Radicals and Pressure

Dr. Fahy devotes a long section to claims that low temperature chemistry is
unfeasible, violates physical law, and isn't what Feynman and Drexler had in
mind!

Feynman never made any statements about temperature, nor did he specify in
any detail how synthesis of arbitrary objects might take place. By contrast,
Drexler's technical book is very specific about the techniques to be employed,
and considers temperature as a significant issue in most settings. Examining
the current draft shows that it will include a chapter on "Mechanochemistry"
with subsections on radicals, carbenes, and other open-shelled (highly reactive)
species; as well as a section on piezochemistry, which will include a section
on force versus thermal activation. While normally of limited use in chemistry,
highly reactive species can be quite useful when their tendency to react with
anything they touch (even at low temperature) is controlled by positional capabilities.

Suppose that we wished to bond two compounds, A and B. Let us presume that
both A and B are closed-shell "stable" compounds, that we are operating in a
high-vacuum low temperature environment, and that we have positional control
available. To create the necessary bond, we might proceed as follows: 1) Abstract
a hydrogen from compound A. (For reasons not entirely clear to me, chemists
like to "abstract" hydrogens with radicals rather them remove them, delete them,
or otherwise dispose of them); 2) Abstract a hydrogen from compound B; 3) Place
compound A next to compound B, with the dangling bonds created by the hydrogen
abstractions of steps (1) and (2) facing each other; 4) Wait for the laws of
physics to do their thing. The activation energy for a radical-radical reaction
is very low, so it doesn't look like we have to worry about the temperature
being too low to support "chemical reactions."

Of course, we need to do an atomically precise hydrogen abstraction for this
procedure to work: how can this be done?

One approach is to use a hydrogen abstraction tool. The basic requirements
for such a tool are clear: one end must be very fond of hydrogen and the other
end must form a "handle" which can be safely grabbed. 1-propynyl (the radical
derivative of propyne) seems to fill the bill (though we will likely wish to
expand the "handle" end of the molecule in some convenient fashion). A carbon
radical triple-bonded to another carbon has an affinity for hydrogen which is
quite high. The bond dissociation energy for the resulting H-C bond is about
132 kilocalories per mole (data were taken from the Handbook of Chemistry
and Physics for the H-C bond in acetylene). Such a structure should be quite
effective as a hydrogen abstraction tool.

This is just one example. Chemistry textbooks that discuss reaction mechanisms
are filled with hydrogen abstractions by radicals. Activation energies for such
abstraction operations can be quite small. Although "normal" compounds don't
react at low temperatures, chemistry using exotic compounds can take place quite
readily.

Of course, we can also apply high pressure. Dr. Fahy said that ". . . pressures
on the order of 15,000 atmospheres are required to convert ice into amorphous
solid water at liquid nitrogen temperature. . ." incorrectly implying that achieving
such pressures should be viewed as difficult. The current record for static
pressure is almost 1.7 million atmospheres (from the Guiness Book of World
Records. Much higher pressures have been achieved dynamically). This pressure
creates forces at the atomic level that are a substantial fraction of the force
required to rupture bonds. We will be able to achieve at least such pressures
in the future, and use them in whatever way seems appropriate during the synthesis
process. A "molecular vise" is not at all unreasonable. By building a diamond-like
"reactive site" that was both extremely hard and whose shape was precisely tailored
to promote a specific reaction, we could "squeeze" two compounds together using
extremely high force that was very precisely applied. This entirely novel form
of synthesis opens yet another broad range of chemical reactions that will occur
at low temperature.

And, of course, we can apply modest pressure to highly reactive radicals, thus
eliminating the need for even the small thermal activation energy called for
in these cases. Chemistry can be done at 0 Kelvin.

Misunderstandings

Many of the criticisms that Dr. Fahy made are based on a massive misunderstanding
of the proposal. He devotes an entire section to specific forms of damage and
the physical problems that would be involved in attempting to directly repair
those forms of damage. However, the major thrust of "Molecular Repair of the
Brain" was precisely to avoid the need to worry about the specific physical
problems in repairing each individual form of damage. Having once gotten a digitized
description of a human brain (and optionally, for those concerned about it,
a "filing cabinet" holding every major macromolecule from that brain), the physical
problems involved in repairing a fractured axon simply don't matter. The component
molecules of the fractured axon now reside in the filing cabinet, while the
coordinate data for the molecules from that fractured axon reside in the data
base describing the frozen structure. "Repair" of the frozen axon, at this stage,
consists of altering the data base. No physical manipulations are called for,
nor would they be useful. Dr. Fahy's concerns are like asking how a computer
text editor can remove the paper when you delete a word. There isn't any paper
to remove. The question, as stated, simply doesn't make sense. You can ask how
the text editor alters the bit-patterns that describe the text. You can ask
about the physical process of printing. But you can't ask how the text editor
changes the printed words on a piece of paper because that's simply not what's
going on.

The alternative to digital modifications of a digital description of the structure
is to directly modify the real physical structure, damage and all. Each specific
form of damage that might occur would require a separate direct physical repair
process. Such a case-by-case analysis is complicated, error prone, and not very
confidence-inspiring. If, however, we digitize the original structure and perform
the "repairs" on the data base, then we can at once eliminate virtually all
problems. The problems that remain are fundamental and are not obscured by a
cloud of secondary issues.

There is one case where direct physical repair of the original structure probably
makes good sense: when the damage that has been done is minimal, is well defined
and well understood, and direct physical repair is not too complicated. One
of the major objectives of research in cryobiology is to minimize the damage
done by freezing and to better characterize that damage. It seems plausible,
therefore, that with continued advances in cryobiology the need for sophisticated
repair methods can be avoided entirely. While we can look forward to that happy
day, it seems unlikely that direct physical repair methods will produce a satisfactory
result when applied to the people suspended using current methods. By contrast,
digitization followed by sophisticated computer analysis and repair is likely
to produce a good result when applied to a person suspended using the current
rather primitive methods (with apologies to those providing us with those much
appreciated primitive methods!). Indeed, sophisticated computer analysis should
produce a satisfactory outcome under remarkably bad circumstances.

Further research aimed at better characterizing and minimizing freezing damage,
as well as aggressive efforts to minimize the damage actually incurred during
suspensions, are both very worthwhile objectives that deserve strong support.
At the same time, it is essential to consider repair methods that will be able
to cope with the most severe damage that might actually occur in practice. By
both minimizing freezing damage and maximizing repair capabilities we will achieve
the highest possible probability of success.

Dr. Fahy has argued that building a brain at low temperature and then warming
it is "nonsensical" because (inter alia) it would explode. Unfortunately for
this argument, extremely rapid warming does not impart momentum per se,
and volume changes caused by temperature changes can be compensated by a number
of mechanisms (e.g., leave space for expansion. . .). The claim that rapid heating
of a biological structure from (say) 130 Kelvins to 340 Kelvins or so will inherently
cause it to explode is without merit.

Much as the rapid heating proposal is charming, a proposal of Dr. Fahy's is
better: build the frozen structure with an appropriate concentration of cryoprotectant
and then heat it slowly. This doesn't have the technical drama of rapid rewarming,
but solves the problem quite effectively. This is, of course, simply one illustration
of a general principle: if you are building a structure using technology X,
then modifications to the structure to make the job easier for that technology
are entirely reasonable. If technology X involves building a frozen structure
and then warming it, then banning structural changes that would allow the structure
to better resist heating would be plain silly. While certain constraints on
the allowed modifications must be made (if the structure is my brain, I have
some strong opinions on some of the constraints!) it should be very clear that
adding cryoprotectants is acceptable.

As an aside, frozen synthesis would allow the cryoprotectant concentration
and even the type of cryoprotectant to be varied from tissue to tissue (or even
cell to cell) to achieve optimal tissue-specific cryoprotectant concentrations.
Combining this with highly controlled (and perhaps quite rapid) heating rates
will result in minimal damage during warming. More sophisticated structural
modifications to make the tissue resistant to warming damage would also be feasible.

Power

"How will nanomachines be powered? No comments from Merkle."

Comment: properly designed electrostatic motors will function quite nicely,
however cold it gets. Electrostatic attraction and repulsion are not altered
by temperature. "Is it feasible in principle to power complex molecular manipulations
. . . at cryogenic temperatures?" Yes. Simple mechanical interactions are not
temperature-dependent. If a probe knob runs into a gate knob, it's blocked regardless
of how low the temperature gets. Rod logic will work quite nicely at liquid
nitrogen temperature.

"Presumably the power would have to be supplied via electrical cables or sliding
rods going in through the vascular system." No. Such a presumption might be
considered for "on board repair." The off board repair method discussed in the
paper eliminates this problem. The structure being examined was taken apart.
The issues surrounding power dissipation were largely eliminated. The volume
occupied by the repair system could greatly exceed the volume occupied by the
brain. The vast bulk of energy dissipation is involved in computation. The computation
can take place as far away from any tissue as we desire.

Time Estimates

Dr. Fahy correctly points out that if repair takes place at low temperature,
then the time estimates based on biological analogies must be viewed with caution.
However, every factor of which I am aware provides a speed advantage to assembler-based
methods, rather than the reverse. As a consequence, the biological times are
extremely conservative estimates of the time that would actually be required
to perform the necessary manipulations. Thermal diffusion and self-assembly
are inherently limited in their speed of operation, and it would be truly remarkable
if future molecular engineering technology did not exceed these speeds by several
orders of magnitude.

Analysis of the fundamental speed limits produces numbers that are shockingly
good (and were not needed to support the basic case). Chemical reactions don't
fundamentally require much time. Femtoseconds and picoseconds are the units
typically used. If we assume one microsecond per chemical reaction, and something
like 1025 chemical reactions to synthesize a structure as large as the human
brain, and if we assume a parallelism of 1016, then we find the job can be
completed in 1000 seconds, or about 17 minutes. There do not appear to be any
fundamental physical reasons to doubt that this will be feasible.

While questions about the fundamental physical limits of computation have attracted
a great deal of interest (for rather obvious economic reasons), no one has yet
(to my knowledge) published a paper discussing the fundamental physical limits
to the speed of synthesis of a complex object. The demonstrated biological speeds
are adequate for our purposes, and tend to be less shocking. While Dr. Fahy
has argued that the biological speeds cannot be used to estimate the rate of
synthesis if non-biological techniques are used, it is in fact reasonable to
view the biological speeds as an upper bound on the synthesis time involved
provided that the non-biological methods are faster. Positionally-based synthesis
techniques should indeed be substantially faster than biological methods, so
the assumption is reasonable.

Other items

Dr. Fahy's claim that building structures at the temperature of liquid nitrogen
is like building them in a black hole is clearly poetic hyperbole and not intended
to be taken seriously.

I'm puzzled by the claim that "removing cracks" is a non-trivial exercise.
It is a trivial exercise. Assignment: given a data base that describes frozen
tissue with cracks, modify it so that it describes the same structure, but without
the cracks. A student in an advanced data structures course might view this
as a reasonably challenging assignment, but any professional in the image analysis
field could toss off half a dozen algorithms for doing the job in an hour. (I
assume the cracks are "clean" low temperature fractures).

The paragraph claiming that rending a molecule asunder at a specific bond is
implausible has rather obviously gone too far. Clearly, given a specific molecule,
and given that we are pulling on it hard enough to rupture a bond, one of two
things will be true. Either: a) two or more bonds are of sufficiently similar
strength that random thermal variations will cause one bond or the other to
actually rupture, thus leading to difficulty in predicting which bond will break,
or; b) one bond is sufficiently weak as compared with other bonds that the weak
bond will always (or very nearly always) break.

Rather obviously, if one wanted a molecule to break at a certain point, one
would design the molecule with a "weak link" at that point. In this way, the
molecule would always break exactly where it was designed to break. Typically,
when a molecule is broken in two in this fashion, the dangling bonds will be
highly reactive radicals that can be used in further reactions. Indeed, rupturing
a molecule with a deliberately designed "weak link" is a good way to reliably
and predictably create specific radicals. In current chemistry, radicals are
often produced by selecting "weak bonds" and breaking them by some process.
Oxygen-oxygen single bonds (peroxides) are fairly popular in this regard. The
use of mechanical methods to rupture weak bonds simply continues an old and
familiar chemical tradition used to generate radicals in support of chemistry.

Conclusion

Dr. Fahy concludes that "From the point of view of a cryobiologist, however,
Merkle's analysis falls far short of being convincing." Evidently, however,
the analysis was convincing as far is it went. The "unconvincing" part was the
part not written: e.g., the synthesis method. Even here, Dr. Fahy seems to agree
that the synthesis of a human brain is feasible. His only objection is that
such synthesis could not be done at low temperature. I have no objections to
synthesis at some other temperature, but the objections he raises to low temperature
synthesis are incorrect. Low temperature synthesis continues to be a synthetic
method with certain advantages (e.g., high precision, stability of intermediate
structures) when compared with other approaches.

This exchange on the subject will not be the last, nor should it be. As repair
scenarios become more detailed, there will be more points of disagreement, not
fewer. Consensus does not emerge at once, full blown. Instead, it emerges bit
by bit, a single piece at a time, as the various issues are argued and discussed
in greater and greater detail.